Salts of 4-Methyl-N-[3-(4-Methyl-Imidazol-1-Yl)-5-Trifluoromethyl-Phenyl]-3-(4-Pyridin-3-Yl-Pyrimidin-2-Ylamino)-Benzamide

ABSTRACT

Salts of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide are prepared by various processes.

This application claims the benefit of U.S. Provisional PatentApplication No. 60/701,406, filed Jul. 20, 2005, the entire disclosureof which is incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to salts of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide,as well as to methods of making the same, pharmaceutical compositionscomprising the same and methods of treatment using the same.

2. Related Background Art

The compound4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamideof the formula

is described in WO 2004/005281 A1. Valuable pharmacological propertiesare attributed to this compound; thus, it can be used, for example, as aprotein kinase inhibitor useful in therapy for diseases which respond toinhibition of protein kinase activity. WO 2004/005281 A1 does notdisclose any specific salts or salt hydrates or solvates of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.

SUMMARY OF THE INVENTION

The present invention is directed to salts of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.Preferred embodiments of the present invention are directed to thehydrochloride, monophosphate, diphosphate, sulfate, methane sulfonate,ethane sulfonate, benzene sulfonate and p-toluene sulfonate salts of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.

The present invention is further directed to a method of preparing avariety of crystalline salts of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidecomprising the step of: reacting4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base with an acid of formula HB in a solvent.

The invention is further directed to pharmaceutical compositionscomprising:

-   -   (a) a therapeutically effective amount of a salt of        4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide;        and    -   (b) at least one pharmaceutically acceptable carrier, diluent,        vehicle or excipient.

The present invention is also directed to a method of treating a diseasewhich responds to an inhibition of protein kinase activity comprisingthe step of administering to a subject in need of such treatment atherapeutically effective amount of a salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the x-ray powder diffraction patterns (XRPDs) for forms Aand B of the hydrochloride salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.

FIG. 2 shows the x-ray powder diffraction pattern (XRPD) for themonophosphate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.

FIG. 3 shows the x-ray powder diffraction pattern for the diphosphatesalt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.

FIG. 4 shows the x-ray powder diffraction patterns for forms A and B ofthe sulfate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.

FIG. 5 shows the x-ray powder diffraction pattern for the methanesulfonate (mesylate) salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.

FIG. 6 shows the x-ray powder diffraction pattern for the ethanesulfonate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.

FIG. 7 shows the x-ray powder diffraction pattern for the benzenesulfonate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.

FIG. 8 shows the x-ray powder diffraction pattern for the p-toluenesulfonate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to salts of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide;preferred embodiments of those salts are described below. Generally, asused herein, “salt” refers to a compound prepared by the reaction of anorganic acid or base drug with a pharmaceutically acceptable mineral ororganic acid or base; as used herein, “salt” includes hydrates andsolvates of salts made in accordance with this invention. Exemplarypharmaceutically acceptable mineral or organic acids or bases are aslisted in Tables 1-8 in Handbook of Pharmaceutical Salts, P. H. Stahland C. G. Wermuth (eds.), VHCA, Zurich, pp. 334-345 (2002). As usedherein, “polymorph” refers to a distinct “crystal modification” or“polymorphic form” or “crystalline form”, which differs from anotherwith respect to x-ray powder diffraction pattern, physicochemical and/orpharmacokinetic properties, and thermodynamic stability. Co-pending U.S.Patent Application No. 60/701,405 (Attorney Docket No. 4-34384), filedconcurrently herewith, addresses the various polymorphic forms of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamideand salts thereof; the disclosure of that co-pending application isincorporated in its entirety by reference herein.

The first embodiment of the present invention is directed to thehydrochloride salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.The hydrochloride salt (form B, monohydrate) is reproducibly producedfrom methanol when one equivalent hydrochloric acid is used. It ishygroscopic (when first tested, moisture uptake was up to 2% at 60%relative humidity and up to 2.7% at 95% relative humidity, thoughsubsequent testing has shown even greater moisture uptake). It is veryslightly soluble in water and slightly soluble in 0.1 N HCl, ethanol and2-propanol. When tested with thermogravimetric analysis (TGA), twoweight loss stages occur. The first stage (onset at about 80° C.)represents dehydration, and the second stage weight loss (at about 173°C.) represents the loss of HCl (decomposition). Its crystal structureranges from good to excellent, it becomes amorphous upon grinding and itcan withstand compression. The hydrochloride salt is stable at roomtemperature in standard equilibration tests. Other polymorphic forms ofthe hydrochloride salt, i.e., forms A, A′, A″, B′, S_(B), S_(B)′, C, C′,S_(C), D, and S_(E), were also isolated. The XRPD pattern for forms Aand B of the hydrochloride salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamideare shown in FIG. 1.

The second embodiment of the present invention is directed to themonophosphate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.The H₃PO₄ mono-salt is reproducibly produced from methanol when oneequivalent phosphoric acid is used. The weight loss (room temperature to200° C.) is about 0.29%, and the sample melts at about 208° C. anddecomposes at about 212° C. Its crystal structure is excellent. The XRPDpattern for the monophosphate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamideis shown in FIG. 2.

The third embodiment of the present invention is directed to thediphosphate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.The H₃PO₄ di-salt can be produced from methanol when two equivalentsphosphoric acid are used. The weight loss (room temperature to 200° C.)is about 0.2%, and the sample decomposes at about 210° C. The XRPDpattern for the diphosphate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamideis shown in FIG. 3.

The fourth embodiment of the present invention is directed to thesulfate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.The H₂SO₄ salt (form B) is reproducibly produced from methanol when oneequivalent sulfuric acid is used. The weight loss (room temperature to200° C.) is about 0.15%, and the sample melts with decomposition atabout 206° C. Its crystal structure ranges from poor to good. One otherform (form A) and an amorphous form were isolated. The XRPD patterns forforms A and B of the sulfate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamideare shown in FIG. 4.

The fifth embodiment of the present invention is directed to the methanesulfonate (mesylate) salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.This salt is reproducibly produced from ethyl acetate when oneequivalent methane sulfonic acid is used. The weight loss (roomtemperature to 150° C.) is about 0.44%, and the sample melts at about160° C. and decomposes at about 260° C. Its crystal structure is poor.The XRPD pattern for the methane sulfonate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamideis shown in FIG. 5.

The sixth embodiment of the present invention is directed to the ethanesulfonate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.This salt is reproducibly produced from ethyl acetate when oneequivalent ethane sulfonic acid is used. The weight loss (roomtemperature to 150° C.) is about 0.74%, and the sample melts at about259° C. and decomposes at about 220° C. Its crystal structure is poor.The XRPD pattern for the ethane sulfonate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamideis shown in FIG. 6.

The seventh embodiment of the present invention is directed to thebenzene sulfonate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.This salt is reproducibly produced from ethyl acetate when oneequivalent benzene sulfonic acid is used. The weight loss (roomtemperature to 250° C.) is about 0.63%, and the sample melts withdecomposition at about 260° C. Its crystal structure ranges from poor togood. The XRPD pattern for the benzene sulfonate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamideis shown in FIG. 7.

The eighth embodiment of the present invention is directed to thep-toluene sulfonate salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.This salt is reproducibly produced from ethyl acetate when oneequivalent p-toluene sulfonic acid is used. The weight loss (roomtemperature to 150° C.) is about 0.26%, and the sample melts at about187° C. and decomposes at about 256° C. Its crystal structure rangesfrom good to excellent. The XRPD pattern for the p-toluene sulfonatesalt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamideis shown in FIG. 8.

Another embodiment of the present invention is directed to a method ofpreparing a variety of crystalline salts of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamideaccording to the following scheme:

More specifically,4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidesalts are made by reacting4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base with an acid of formula HB in a solvent. Such reaction istypically conducted in two steps, though it is within the scope of thisinvention to simply combine both the free base and the acid in thesolvent at the same time.

In a first step,4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base is dissolved or suspended in an appropriate amount of solventat an appropriate temperature. Solvents suitable for use in the presentinvention include, without limitation, methanol, ethanol, 2-propanol,acetone, ethyl acetate, acetonitrile, tetrahydrofuran and combinationsthereof. It is within the skill of one of ordinary skill in the art todetermine suitable amounts of base to be used, as well as suitablereaction temperatures.

In a second step of the present inventive method, the4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base is treated with an appropriate acid of the formula HB. Giventhe pKa values for4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base of 5.1 and 3.9, salt forming acids with a pKa of ≦3.1 have thepotential to form stable crystalline salts therewith. Suitable acidsinclude, without limitation, inorganic acids such as hydrochloric acid,phosphoric acid, sulfuric acid, and sulfonic acid and organic acids suchas methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid,p-toluene sulfonic acid, citric acid, fumaric acid, gentisic acid,malonic acid, maleic acid, and tartaric acid.

In optional steps of the present inventive method, the4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidesalt is isolated by filtration or some other suitable means and theisolated salt is dried to remove residual solvent. In a preferredembodiment of this invention, the hydrochloride salt is first obtainedas a methanol solvate which must be exposed to moisture in order toconvert to the monohydrate hydrochloride salt.

A particularly preferred embodiment of the present invention is directedto a method of preparing4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidemonohydrochloride monohydrate comprising the steps of:

-   -   (a) combining        4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide        free base and hydrochloric acid in methanol under a nitrogen        atmosphere;    -   (b) heating the reaction mixture to a temperature ranging from        about 42-50° C.;    -   (c) stirring the reaction mixture;    -   (d) filtering the reaction mixture while maintaining the        temperature above 40° C. to obtain a clear solution;    -   (e) cooling the clear solution to about 30° C. while stirring        under nitrogen atmosphere;    -   (f) seeding the solution;    -   (g) cooling the seeded solution to about 23° C.;    -   (h) stirring the solution to obtain a suspension;    -   (i) cooling the suspension to about −10° C.;    -   (j) stirring the suspension;    -   (k) filtering solids;    -   (l) rinsing solids with cold methanol; and    -   (m) drying the solids at about 50-55° C. and 10-20 torr to        obtain        4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide        monohydrochloride monohydrate salt.        In more preferred embodiments, stirring is conducted for about        15 minutes in step (c), cooling is accomplished over a period of        about 30 minutes in step (e), cooling is accomplished over a        period of about 45 minutes in step (g), stirring is conducted        for about 3 hours in step (h), cooling is accomplished over a        period of about 1.5 hours in step (i), stirring is conducted for        about 30 minutes in step k), the cold methanol of step (l) has a        temperature of about −10° C., and/or drying is accomplished over        a period of about 8-16 hours.

The tenth embodiment of the present invention is directed to apharmaceutical composition comprising:

-   -   (a) a therapeutically effective amount of a salt of        4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide;        and    -   (b) at least one pharmaceutically acceptable carrier, diluent,        vehicle or excipient.

A “therapeutically effective amount” is intended to mean the amount ofthe inventive salt that, when administered to a subject in need thereof,is sufficient to effect treatment for disease conditions alleviated bythe inhibition of protein kinase activity. The amount of a givencompound of the invention that will be therapeutically effective willvary depending upon factors such as the disease condition and theseverity thereof, the identity of the subject in need thereof, etc.,which amount may be routinely determined by artisans of ordinary skillin the art.

The at least one pharmaceutically acceptable carrier, diluent, vehicleor excipient can readily be selected by one of ordinary skill in the artand will be determined by the desired mode of administration.Illustrative examples of suitable modes of administration include oral,nasal, parenteral, topical, transdermal, and rectal. The pharmaceuticalcompositions of this invention may take any pharmaceutical formrecognizable to the skilled artisan as being suitable. Suitablepharmaceutical forms include solid, semisolid, liquid, or lyophilizedformulations, such as tablets, powders, capsules, suppositories,suspensions, liposomes, and aerosols.

The eleventh embodiment of the present invention is directed to a methodof treating a disease which responds to an inhibition of protein kinaseactivity comprising the step of administering to a subject in need ofsuch treatment a therapeutically effective amount of a salt of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.As noted above, illustrative modes of administration include oral,nasal, parenteral, topical, transdermal, and rectal. Administration ofthe crystalline form may be accomplished by administration of apharmaceutical composition of the ninth embodiment of the invention orvia any other effective means.

Specific embodiments of the invention will now be demonstrated byreference to the following examples. It should be understood that theseexamples are disclosed solely by way of illustrating the invention andshould not be taken in any way to limit the scope of the presentinvention.

EXAMPLE 1 Preparation of Monohydrochloride Monohydrate Salt

A 1 L, 4-neck, round-bottom flask equipped with a mechanical stirrer, athermometer, heating/cooling capacity, and an addition funnel wascharged in sequence with4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base (10 g), methanol (250 mL), and 37% hydrochloric acid (1.85 g)under nitrogen purge. The mixture was heated to 42-50° C. and stirredfor an additional 15 minutes. The resulting solution was filteredthrough a polypropylene pad, while maintaining the batch temperatureabove 40° C. The clear solution was transferred under nitrogenatmosphere to another 1 L, 4-neck, and round-bottom flask equipped witha mechanical stirrer, a thermometer, and heating/cooling capacity. Thebatch was stirred and cooled to 30° C. over a period of 30 minutes.Seeds (20 mg) were added at this temperature, and the batch was cooledto 23° C. over a period of 45 minutes. The batch was stirred for anadditional 3 hours to obtain a thick white suspension. The suspensionwas cooled to −10° C. over a period of 1.5 hours and stirred for anadditional 30 minutes. Any solid was collected by filtration and rinsedwith cold (−10° C.) methanol (20 mL). The solid was dried at 50-55°C./10-20 torr for 8-16 hours to obtain4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidemonohydrochloride monohydrate salt (9.8 g) as a white solid.

¹H NMR 300 MHz, DMSO-d₆), δ 10.9 (s, 1H), 9.58 (s, 1H), 9.29 (s, 1H),9.20 (s, 1H), 8.70 (d, 1H), 8.63 (s, 1H), 8.55 (d, 1H), 8.49 (d, 1H),8.32 (d, 2H), 8.00 (s, 1H), 7.91 (s, 1H), 7.84 (d, 1H), 7.56-7.44 (m,3H), 2.50 (s, 3H), 2.35 (s, 3H); x-ray diffraction pattern showingmaxima at 2θ=7.4°, 9.4°, 11.6°, 12.1°, 15.8°, 19.3°, 19.6°, 22.1°,24.1°, 25.7°.

EXAMPLE 2 Preparation of Monophosphate Salt

To a 1 L round-bottom flask equipped with a mechanical stirrer, athermometer, and a condenser, 4 g of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base and 500 mL of methanol were charged. The slurry was stirredand heated to 64° C. and held at that temperature for ˜30 minutes. Tothe resulting clear solution, 7.5 mL of 1 M phosphorous acid solution(in methanol) was added. The mixture was stirred at 64° C. for one hour,cooled down to room temperature by natural cooling (cooling rate ˜0.5°C./min) and held at room temperature for 3-4 hours. The solid wascollected by filtration and was dried at 50-55° C./10-20 torr for 8-16hours to obtain4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidemonophosphate salt (3.25 g) as a white solid. Melting point=˜208° C.(dec.); x-ray diffraction pattern showing maxima at 2θ=6.1°, 7.5°, 9.1°,15.8°, 17.5°, 18.3°, 21.8°, 23.1°, 24.9°, 26.6°.

EXAMPLE 3 Preparation of Methane Sulfonate Salt

To a 75 mL reactor equipped with a temperature probe and a condenser,307 mg of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base and 30 mL of ethyl acetate were charged. The slurry wasstirred and heated to 76° C. To the solution, 580 μL of 1 M methanesulfonic acid solution (in ethyl acetate) was added. The mixture wasstirred at 76° C. for six hours, cooled to 25° C. at a rate of 0.5°C./minute and held at 25° C. overnight. The solid was collected byfiltration and was dried at 50-55° C./10-20 torr for 8-16 hours toobtain4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidemesylate salt (˜250 mg) as a yellowish solid. X-ray diffraction patternshowing maxima at 2θ=7.7°, 10.1°, 20.3°, 26.2°.

EXAMPLE 4 Preparation of Benzylsulfonate Salt

To a 1 L round-bottom flask equipped with a mechanical stirrer, athermometer, and a condenser, 4 g of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base and 500 mL of ethyl acetate were charged. The slurry wasstirred and heated to 76° C. (reflux) and held at that temperature for40 minutes. To the resulting clear solution, 7.5 mL of 1 M benzenesulfonic acid solution (in ethyl acetate) was added. The mixture wasstirred at 76° C. for 5 hours, cooled down to room temperature bynatural cooling (cooling rate ˜0.5° C./min) and held at room temperaturefor ˜1 hour. The solid was collected by filtration and was dried at50-55° C./10-20 torr for 8-16 hours to obtain4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidemono benzyl sulfonate salt as a yellowish solid. Melting point=˜260° C.;x-ray diffraction pattern showing maxima at 2θ=6.5°, 7.8°, 9.4°, 10.4°,13.7°, 17.0°, 17.5°, 17.9°, 18.8°, 21.2°.

EXAMPLE 5 Preparation of p-Toluene Sulfonate Salt

To a 75 mL reactor equipped with a temperature probe and a condenser,305.6 mg of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base and 30 mL of ethyl acetate were charged. The slurry wasstirred and heated to 76° C. To the solution, 580 μL of 1 M p-toluenesulfonic acid solution (in ethyl acetate) was added. The mixture wasstirred at 76° C. for six hours, cooled to 25° C. at a rate of 0.5°C./minute and held at 25° C. overnight. The solid was collected byfiltration and was dried at 50-55° C./10-20 torr for 8-16 hours toobtain4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidep-toluene sulfonate salt (˜250 mg) as a white solid. Melting point=˜187°C.; x-ray diffraction pattern showing maxima at 2θ=7.3°, 15.4°, 16.1°,17.5°, 18.3°, 19.0°, 19.7°, 22.5°.

EXAMPLE 6 Hydrochloride Salt

4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base and about 400 mL methanol are charged into a flask. Whilestirring, 744.4 mg of 37% HCl solution is added dropwise. The slurrybecomes clear. The solution is stirred for 30 minutes. The solution isconcentrated to 100 mL. The solution is then stirred for 2 hours; aslurry is obtained. The slurry is filtered and dried under house vacuumovernight at 50° C. Polymorphic form B is obtained with a yield of about72.6%.

EXAMPLE 7

About 50-60 mg of form A of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base was suspended in 0.75 mL of a listed solvent. Thestoichiometric amount of a noted acid was subsequently added to thesuspension. For inorganic acids, the mixture was stirred at ambienttemperature for about 5 hours, and for sulfonic acids, it was stirred at50° C. overnight. Solids were collected by filtration and analyzed byXRPD and NMR.

TABLE 1 Formation of Hydrochloride Salt Results Solvent CommentsCrystallinity* ¹H-NMR Methanol Slurry becomes thinner after HCladdition. Good; form B No solvent peak Ethanol Slurry becomes thinnerafter HCl addition. Good; forms A & B No solvent peak 2-Propanol Slurrybecomes thinner after HCl addition. Good; form A No solvent peak AcetoneSlurry becomes thinner after HCl addition. Excellent; form A — Ethylacetate Slurry becomes thinner after HCl addition. Good; forms A & B —Tetrahydrofuran Slurry becomes thinner after HCl addition. Excellent;form A — Acetonitrile Slurry becomes thinner after HCl addition.Excellent; forms A & B — *excellent = when main peaks are sharp andtheir intensities above 70 counts good = when main peaks are sharp andtheir intensities within 30-70 counts

TABLE 2 Formation of Sulfate Salt Results Solvent CommentsCrystallinity* ¹H-NMR Methanol Slurry becomes thinner after H₂SO₄addition. Good; forms A & B No solvent peak Ethanol Slurry becomesthinner after H₂SO₄ addition. Good; form B No solvent peak 2-PropanolSlurry becomes thinner after H₂SO₄ addition. Poor — Acetone Slurrybecomes thinner after H₂SO₄ addition. Poor — Ethyl acetate Slurrybecomes thinner after H₂SO₄ addition. Poor — Tetrahydrofuran Slurrybecomes thinner after H₂SO₄ addition. Poor — Acetonitrile Slurry becomesthinner after H₂SO₄ addition. Poor — *good = when main peaks are sharpand their intensities within 30-70 counts poor = when main peaks arebroad and their intensities below 30 counts; could be amorphous salt andfree base form A

TABLE 3 Formation of Methane Sulfonate Salt Results Solvent CommentsCrystallinity* ¹H-NMR Acetone Slurry became thinner and turned yellowafter Poor 1) 1.3% (w) acetone acid addition. It did not become clear at50° C. 2) acid:base = 1.2:1.0 Tetrahydrofuran Slurry became thinner andturned yellow after Amorphous — acid addition. It did not become clearat 50° C. *poor = when main peaks are broad and their intensities below30 counts

TABLE 4 Formation of Ethane Sulfonate Salt Results Solvent CommentsCrystallinity* ¹H-NMR Acetone Slurry became thinner and turned yellowafter Good 1) 0.9% (w) acetone acid addition. It did not become clear at50° C. 2) acid:base = 1.4:1.0 Tetrahydrofuran Slurry became thinner andturned yellow after Poor — acid addition. It did not become clear at 50°C. *good = when main peaks are sharp and their intensities within 30-70counts poor = when main peaks are broad and their intensities below 30counts

The ethane sulfonate salt from acetone has an x-ray diffraction patternshowing maxima at 2θ=6.6°, 7.9°, 9.5°, 14.2°, 17.8°.

TABLE 5 Formation of Benzene Sulfonate Salt Results Solvent CommentsCrystallinity* ¹H-NMR Tetrahydrofuran Slurry became thinner and turnedyellow after Poor 1) 1.2% (w) THF acid addition. It did not become clearat 50° C. 2) acid:base = 1.4:1.0 Acetone Slurry became thinner andturned yellow after Poor — acid addition. It did not become clear at 50°C. *poor = when main peaks are broad and their intensities below 30counts

TABLE 6 Formation of p-Toluene Sulfonate Salt Results Solvent CommentsCrystallinity* ¹H-NMR Tetrahydrofuran Slurry became thinner after acidaddition. It Good 1) 4.6% (w) THF did not become clear at 50° C. Whitesolid 2) acid:base = 1.2:1.0 was obtained by filtration. Acetone Slurrybecame thinner after acid addition. It Good — did not become clear at50° C. White solid was obtained by filtration. *good = when main peaksare sharp and their intensities within 30-70 counts

EXAMPLE 8

About 300-310 mg of form B of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base was suspended in 9 mL of 2-propanol for HCl and 15 mL acetonefor the sulfonic acids. The stoichiometric amount of the noted acid wassubsequently added to the suspension. For HCl, the mixture was stirredat ambient temperature for 5 hours, and for sulfonic acids, it wasstirred at 50° C. overnight. Then, the mixture was cooled to ambienttemperature, collected by filtration and analyzed by XRPD and NMR.

TABLE 7 Results Acid Comments Crystallinity ¹H-NMR HCl After HCladdition, the slurry became 1) good 1) shifts changed yellow, thenoff-white. After 4 hours 2) form A 2) no solvent peak of holding, theslurry was like paste, difficult to pour and filter. Methane sulfonicacid Slurry became thinner and turned Poor 1) shifts changed yellowafter acid addition. It did not 2) 0.67% (w) acetone become clear at 50°C. Ethane sulfonic acid Slurry became thinner and turned Poor 1) shiftschanged yellow after acid addition. It did not 2) no solvent peak becomeclear at 50° C. p-Toluene sulfonic acid Slurry became thinner and turnedGood 1) shifts changed yellow after acid addition. It did not 2) nosolvent peak become clear at 50° C. White solid was obtained byfiltration.

EXAMPLE 9

About 100 mg of form B of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base was suspended in 15 mL of methanol for the inorganic acids andin 15 mL THF for the sulfonic acids noted below. The stoichiometricamount of the listed acid was subsequently added to the suspension,except for H₃PO₄, for which two equivalents were added. The solution wasstirred at 50° C. for about 5 hours and then cooled to ambienttemperature. Solids were collected by filtration if slurry formed;otherwise, a slow N₂ flow was applied to evaporate some solvent to yieldthicker slurry for filtration. The solids were analyzed by XRPD and NMR.

TABLE 8 Results Acid Comments Crystallinity ¹H-NMR HCl The slurry becameclear while 1) good 1) shifts changed heating and remained so. Slow N₂2) Form B 2) no solvent peak flow was used to evaporate some solvent.H₂SO₄ The slurry became clear after 1) good 1) shifts changed heating.It became slurry during 2) form A + B 2) <2% methanol cooling. H₃PO₄(diphosphate) Slurry becomes thicker after acid 1) excellent 1) no shiftchange addition. 2) different from 2) no solvent peak free base andmono-salt Methane sulfonic acid Slurry became thinner and turned Poor 1)shifts changed yellow after acid addition. It did not 2) no solvent peakbecome clear at 50° C. Benzene sulfonic acid Slurry became thinner andturned Good 1) shifts changed yellow after acid addition. It did not 2)no solvent peak become clear at 50° C. p-Toluene sulfonic acid Slurrybecame thinner and turned Excellent 1) shifts changed yellow after acidaddition. It did not 2) no solvent peak become clear at 50° C. Whitesolid was obtained by filtration.

Elemental analysis was used to check salt formation for the diphosphatesalt. The results are as follows:

TABLE 9 C H N P Theoretical 45.91 3.83 13.39 8.47 H₃PO₄ above 45.86 3.8113.32 9.01

EXAMPLE 10

About 100 mg of form B of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base was suspended in 15 mL of methanol for HCl and H₂SO₄ and in 15mL of ethyl acetate for methane sulfonic acid. The listed amount of thelisted acid was subsequently added to the suspension. The solution wasstirred at ambient temperature (HCl) or 50° C. (H₂SO₄ and methanesulfonic acid). The solids were obtained by evaporating solvent todryness using a slow N₂ flow and analyzed by XRPD and NMR.

TABLE 10 Results Acid Comments Crystallinity ¹H-NMR 1 equivalent HCl Theslurry became clear while 1) good 1) shifts changed heating and remainedso. 2) form B 2) no solvent peak 2 equivalents HCl The slurry becameclear while Amorphous — heating and remained so. 0.5 equivalents H₂SO₄The slurry became clear while 1) good 1) shifts changed heating andremained so. 2) form A & 2) small solvent peak free base form B 1equivalent H₂SO₄ The slurry became clear after acid 1) good 1) shiftschanged addition and remained so. 2) form A 2) no solvent peak 1equivalent methane Slurry became clear after acid Poor 1) acid:base =1.3:1.0 sulfonic acid addition and remained so after 2) no solvent peak4 hours holding. 2 equivalents methane Slurry became clear after acidPoor 1) acid:base = 1.9:1.0 sulfonic acid addition and remained so after2) no solvent peak 4 hours holding.

EXAMPLE 11

About 300 mg of form B of4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base was suspended in 30 mL of methanol for the inorganic acids andin 30 mL ethyl acetate for the sulfonic acids. The suspension was heatedto reflux temperature −64° C. for methanol and 76° C. for ethyl acetate.The stoichiometric amount of the listed acid, dissolved in thecorresponding solvent, was subsequently added to the solution. Thesolution was stirred under reflux for 5 hours and then cooled to ambienttemperature. The solid was collected by filtration and analyzed by XRPD.

TABLE 11 Acid Comments Form H₂SO₄ The slurry became clear under reflux.Solid 1) sulfate precipitated out after holding. 2) form B H₃PO₄ Theslurry became clear under reflux. Solid Monophosphate precipitated outafter holding. Methane sulfonic acid The solution remained slurry underreflux. It Methane sulfonate became thinner and turned yellow after acidaddition. Benzene sulfonic acid The solution remained slurry underreflux. It Benzene sulfonate became thinner and turned yellow after acidaddition. p-Toluene sulfonic acid The solution remained slurry underreflux. It p-Toluene sulfonate became clear after acid addition.

Thermal Behavior

The LOD and decomposition temperature of the salts of the invention weredetermined by TGA, and the melting point was determined by DSC.

TABLE 12 Decomposition Melting temperature point Salt LOD (° C.)* (° C.)Hydrochloride 2.60% (RT-150° C.) (form B) 4.87% (150-250° C.)Monophosphate 0.29% (RT-200° C.) 212 ~208 Sulfate (form B) 0.15%(RT-200° C.) 201 1) 126.5 2) 206.2 Methane sulfonate 0.44% (RT-150° C.)260 160.1 Ethane sulfonate 0.74% (RT-150° C.) 220 1) 259.2 2) 261.3Benzene sulfonate 0.63% (RT-250° C.) 260 >258.7 p-Toluene sulfonate0.26% (RT-150° C.) 256 1) 187 2) 232 *The decomposition temperature wasdetermined by the onset of the first derivative of the sample weightloss v. temperature of TGA data

Hygroscopicity

The hygroscopicity of the salts of the invention was determined by TGAafter one day at ambient temperature and 93% relative humidity.

TABLE 13 Salt % moisture gain Hydrochloride (form B) 0.20 Monophosphate1.33 Sulfate (form B) 0.22 Methane sulfonate 0.22 Ethane sulfonate 1.11Benzene sulfonate 0.11 p-Toluene sulfonate 1.02 Control - free base formB 0.08

It should be noted that, upon further testing, hygroscopicity resultshave varied. At least with regard to the hydrochloride salt, moisture islost too quickly upon testing to capture the true value; such may betrue for the other salts as well.

Solubility

The solubility of the salts of the invention was determined in pH 6.8,pH 3.0 and pH 1.0 buffers by suspending 1-5 mg of each salt in 10 mL ofcorresponding aqueous solution. The samples were allowed to equilibrateat ambient temperature for at least 20 hours for pH 6.8 and 3.0 or about5 hours for pH 1.0. The supernatant was filtered and used for thesolubility determination by UV-VIS spectroscopy. The solid residue wasanalyzed by XRPD.

TABLE 14 Solubility Solubility at pH 6.8 Solubility at pH 3.0 at pH 1.0Solute (μg/mL) (μg/mL) (μg/mL) Hydrochloride salt (form B) 0.3 0.9 1040Monophosphate salt — — 1160 Sulfate salt (form B) 0.1 6.5 1380 Methanesulfonate salt 0.4 5.2 1330 Ethane sulfonate salt 0.4 2.8 — Benzenesulfonate salt <3.0   — 1420 p-Toluene sulfonate salt <8.0   <10.0   1340 Control - free base form B 0.2 2.8  839

Comparative Testing

The stability of both4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base (form B) and4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidemonohydrate hydrochloride salt (form B) were evaluated as describedbelow.

TABLE 15 Salt form Hydrochloride monohydrate Free base (form B) (form B)Degradation products Degradation products Test conditions Assay [% area]Appearance Assay [% area] Appearance Unstressed 0.00 — 0.00 — 100.99[100.00] 99.10 [100.00] 0.1% solutions or suspensions, 1 week at 80° C.pH 1 (pH measured: 1.26) 60.61  A* 62.06  A* PH 1; 1 week @ 50° C. 50.22[45.31] A* 46.68 [42.93] A* 6.58 6.86 94.01 [93.44] 94.14 [93.21] pH 2(pH measured: 2.00) 5.20 B↓ 8.41 B↓ 96.00 [94.86] 91.77 [91.61] pH 3 (pHmeasured: 2.94) 0.00 A↓ 0.00 B↓ 102.19 [100.00]  98.84 [100.00] pH 5 (pHmeasured: 5.01) 0.00 A↓ 0.00 A↓ 100.80 [100.00] 100.02 [100.00] pH 7 (pHmeasured: 6.02) 0.00 A↓ 0.00 B↓ 100.14 [100.00]  99.56 [100.00] pH 9 (pHmeasured: 8.92) 0.00 A↓ 0.00 B↓  99.19 [100.00] 101.19 [100.00] pH 11(pH measured: 0.00 A↓ 0.00 B↓ 10.86) 100.50 [100.00] 102.19 [100.00]Water (pH measured: 0.00 A↓ 0.00 A↓ 4.74)(pH measured for HCl 101.93[100.00] 101.43 [100.00] salt: 4.22) Ethanol 0.04 A* 0.06 A* 99.85[99.96] 100.41 [100.00] Acetonitrile 0.00 A* 0.00 B↓ 100.16 [100.00]100.33 [100.00] Methanol 1.06 A* 1.29 A* 98.04 [98.90] 99.169 [98.72] 2% solutions or suspensions, 1 day at room temperature 0.5% CMC 0.00 A↓0.00 A↓  98.28 [100.00] 103.06 [100.00] 0.5% HPMC cellulose 0.00 A↓ 0.00A↓ 4000  98.27 [100.00] 100.44 [100.00] 0.8% Tween 80 0.00 A↓ 0.00 A↓ 98.78 [100.00] 102.42 [100.00] 5% solutions in DMSO, 1 day at roomtemperature 1:100 dilution in pH 6.8 0.00 A↓ 0.00 A↓ buffer  96.98[100.00] 101.85 [100.00] Solid state, 1 week 80° C., tight containerBulk (HPLC) 0.00 A 0.00 A  99.77 [100.00] 100.77 [100.00] Bulk (XRPD) Nochange No change 30% in mixture 1 0.00 A 0.00 A 100.11 [100.00] 101.23[100.00] 30% in mixture 2 2.17 A 2.08 A 94.28 [97.75] 93.43 [97.82]Solid state, 1 week 80° C., 75% relative humidity Bulk (HPLC) 0.00 A0.00 A  99.97 [100.00] 100.71 [100.00] Bulk (XRPD) No change No change30% in mixture 1 0.00 B 0.00 B  99.38 [100.00] 100.88 [100.00] 30% inmixture 2 3.71 B 1.89 B 89.37 [96.02] 92.17 [97.99] Xenon light(approximately 1200 kLuxh) Bulk (HPLC) 0.00 A 0.00 A  96.03 [100.00] 99.73 [100.00] Bulk (XRPD) No change No change Bulk corrosivity 2 day,80% relative N/A No change humidity with steel coupon ↓suspension A nochange of color *clear solution after stress test B slight discolorationMixture 1: 30%4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide(free base or salt), 63% lactose 100 mesh/lactose 200 mesh (50:50), 5%crosprovidone, 1% Aerosil 200, 1% magnesium stearate Mixture 2: 30%4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide(free base or salt), 34% mannitol 60, 34% Avicel PH102, 1% Aerosil 200,1% magnesium stearate (% by weight of free base or salt)

TABLE 16 Forced Decomposition Test Degradation Test condition Appearanceproducts Assay [% area] Unstressed 0.00 (0)  99.22 [100.00] Bulk A 0.00(0)  99.02 [100.00] 3 days/100° C. 10 mg/1.5 mL DMSO + 0.5 mL water A*0.75 (4) 97.04 [99.24] 3 days/100° C. 10 mg/1.5 mL DMSO + 0.5 mL 0.1 NHCl A* 11.64 (7)  89.15 [88.45] 3 days/50° C. A* 0.00 (0) 100.04[100.00] 10 mg/1.5 mL DMSO + 0.5 mL 0.1 N NaOH A* 6.79 (3) 94.64 [93.30]3 days/50° C. 10 mg/1.5 mL DMSO + 0.5 mL water A* 1.66 (5) 96.89 [98.32]containing 200 ppm Fe³⁺, Ni²⁺ and Cu²⁺ saturated with O₂ 3 days/100° C.10 mg/1.5 mL DMSO + 0.5 mL water A* 0.58 (2) 99.37 [99.42] saturatedwith 0₂ 3 days/100° C. 10 mg/1.5 mL DMSO + 0.5 mL 10% H₂O₂ B* 0.34 (2)98.85 [99.66] 3 days/100° C. 10 mg/1.5 mL DMSO + 0.5 mL water B* 2.74(5) 96.10 [97.23] xenon light (1200 kLux)

The chemical, physicochemical and morphic characteristics of both4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidefree base (form B) and4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidemonohydrate hydrochloride salt (form B) were evaluated as describedbelow.

Determination of Approximate Solubility: A weighted amount (20-50 mg) ofsample was charged into 2 mL of the solvent. The obtained slurry wasallowed to equilibrate for 24 hours at room temperature and thenfiltered. The concentration of DS in saturated filtrate was measured byeither UV or HPLC.

Intrinsic Dissolution Rate (IDR): Dissolution rate measurements wereperformed at 37° C. using the rotating disk method (VanKell Instrument).A single rotation speed of 200 rpm was used. For IDR in 0.1 N HCl, an800 mL volume, and for IDR in water, a 200 mL volume were used. Thesolution was continuously pumped through a UV measuring cell andrecycled to the dissolution vessel.

Hygroscopicity: Sorption/desorption isotherms were collected using aSurface Measurements Systems dynamic vapor sorption device (DVS-1). Themeasurements were carried out at 25° C.

TABLE 17 Chemical and Physicochemical Characteristics Salt formHydrochloride Parameter Free base form B monohydrate (form B) Elementaryanalysis Calculated Found Calculated Found % C 63.46 63.58 57.58 57.66 %H 4.15 3.97 4.29 4.25 % F 10.76 10.22 9.77 9.83 % N 18.51 18.57 16.8016.58 % O 3.02 3.56 5.48 5.68 % Cl N/A N/A 6.08 6.00 DSC purity (mol %)98.65 N/A due to (10° C./minute) decomposition prior to melting HPLCpurity (area %) 100.00 100.00  DSC melting point (° C.) 249.0 N/A due to(10° C./minute) decomposition prior to melting Melting enthalpy (J/g)153.9 N/A due to decomposition prior to melting pH of 1% solution or7.99 2.53 suspension in water Solubility (approximately at 25° C.,mg/mL) 0.1 N HCl 0.60 0.94 0.01 N HCl 0.0014 0.08 Phosphate buffer, pH6.8 0.0002 Below detection Water Below detection 0.17 Ethanol 0.63 3.69Isopropanol 0.33 1.93 Thermogravimetry 0.026 0.91 (weight loss %) (RT to200° C.) (RT to 80° C.) (10° C./minute) Residual solvents (%) 0.2 0.0 Intrinsic dissolution rate (mg min⁻¹cm⁻²) pH 1 (0.1 N HCl) 0.17 0.17Water 0.0013  0.0024

While the invention has been described above with reference to specificembodiments thereof, it is apparent that many changes, modifications,and variations can be made without departing from the inventive conceptdisclosed herein. Accordingly, it is intended to embrace all suchchanges, modifications, and variations that fall within the spirit andbroad scope of the appended claims. All patent applications, patents,and other publications cited herein are incorporated by reference intheir entirety.

1. A salt of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.
 2. The salt of claim 1, wherein the salt is a hydrochloride salt of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.
 3. The salt of claim 2, wherein the salt is 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide monohydrochloride monohydrate.
 4. The salt of claim 1, wherein the salt is a monophosphate salt of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.
 5. The salt of claim 1, wherein the salt is a diphosphate salt of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.
 6. The salt of claim 1, wherein the salt is a sulfate salt of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.
 7. The salt of claim 1, wherein the salt is a methane sulfonate salt of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.
 8. The salt of claim 1, wherein the salt is an ethane sulfonate salt of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.
 9. The salt of claim 1, wherein the salt is a benzene sulfonate salt of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.
 10. The salt of claim 1, wherein the salt is a p-toluene sulfonate salt of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide.
 11. A method of preparing a salt of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide comprising the step of: reacting 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base with an acid of formula HB in a solvent.
 12. The method of claim 11, wherein the acid is selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, sulfonic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, citric acid, fumaric acid, gentisic acid, malonic acid, maleic acid, and tartaric acid.
 13. A method of preparing 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide monohydrochloride monohydrate comprising the steps of: (a) combining 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base and hydrochloric acid in methanol under a nitrogen atmosphere; (b) heating the reaction mixture to a temperature ranging from about 42-50° C.; (c) stirring the reaction mixture; (d) filtering the reaction mixture while maintaining the temperature above 40° C. to obtain a clear solution; (e) cooling the clear solution to about 30° C. while stirring under nitrogen atmosphere; (f) seeding the solution; (g) cooling the seeded solution to about 23° C.; (h) stirring the solution to obtain a suspension; (i) cooling the suspension to about −10° C.; (j) stirring the suspension; (k) filtering solids; (l) rinsing solids with cold methanol; and (m) drying the solids at about 50-55° C. and 10-20 torr to obtain 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide monohydrochloride monohydrate salt.
 14. A pharmaceutical composition comprising: (a) a therapeutically effective amount of a salt according to claim 1; and (b) at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient.
 15. The pharmaceutical composition of claim 14, wherein the salt is 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide monohydrochloride monohydrate.
 16. A method of treating a disease which responds to an inhibition of protein kinase activity comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of a salt according to claim
 1. 17. The method of claim 16, wherein the salt is 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide monohydrochloride monohydrate. 